Pyrazolopyrimidine kinase inhibitors

Abstract

The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

We claim: 
     
       1. A compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is —H, halogen, —CN, —NO 2 , —OR′, —N(R′) 2 , —C(O)OR′, —C(O)N(R′) 2 , —NR′C(O)R′, —NR′C(O)OR′, C1-C10 aliphatic optionally and independently substituted with one or more J a ; 
 ring B is a 6-membered monocyclic heteroaromatic ring optionally fused to an aromatic or non-aromatic ring; and ring B is optionally substituted with one Y and independently further optionally and independently substituted with one or more J c ; 
 Y is —Y1-Q1; 
 Y1 is absent, or C1-10 aliphatic, wherein up to three methylene units of Y1 are optionally and independently replaced with G′ wherein G′ is —O—, —C(O)—, —N(R′)—, or —S(O) p —; and Y1 is optionally and independently substituted with one or more J d ; 
 Q1 is absent, or a C3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Q1 is optionally and independently substituted with one or more J b ; wherein when B is substituted with Y then Y1 and Q1 are not both absent; 
 ring C is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and ring C is optionally substituted with one Z and independently further optionally and independently substituted with one or more J b ; 
 Z is —Y2-Q2; 
 Y2 is absent, or C1-10 aliphatic, wherein up to three methylene units of Y2 are optionally and independently replaced with G′ wherein G′ is —O—, —C(O)—, —N(R′)—, or —S(O) p —; and Y2 is optionally and independently substituted with one or more J d ; 
 Q2 is absent, C3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Q2 is optionally and independently substituted with one or more J e ; wherein when C is substituted with Z then Y2 and Q2 are not both absent; 
 each R′ is independently —H, or C1-C6 alkyl optionally and independently substituted with one or more J a ; 
 each J a  is independently halogen, —OR, —N(R) 2 , —C(O)R, —C(O)OR, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)OR, —CN, —NO 2 , or oxo; 
 each J b  is independently halogen, —OR, —CF 3 , —N(R) 2 , —C(O)R, —C(O)OR, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)OR, —CN, —NO 2 , oxo, or C1-C6 alkyl optionally and independently substituted with one or more J a ; or 
 two J b  groups on the same atom can join together to form a C3-8 membered partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally and independently substituted with one or more J a ; 
 each J c  is independently halogen, —OR′, —N(R) 2 , —C(O)R, —C(O)OR′, —C(O)N(R′) 2 , —NR′C(O)R′, —NR′C(O)OR′, —CN, —NO 2 , or C1-C10 aliphatic optionally and independently substituted with one or more J a , or C3-C8 cycloaliphatic optionally and independently substituted with one or more J b ; 
 each J d  is independently halogen, —OR, —N(R) 2 , —C(O)R, —C(O)OR, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)OR, —CN, or —NO 2 ; 
 each J e  is independently halogen, —OR, —N(R) 2 , —C(O)R, —C(O)OR, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)OR, —CN, —NO 2 , oxo, C1-10 aliphatic, wherein up to three methylene units are optionally and independently replaced with G′ wherein G′ is —O—, —C(O)—, —N(R′)—, or —S(O) p — and the aliphatic group is optionally and independently substituted with one or more J d , or J e  is C3-8 cycloaliphatic optionally and independently substituted with one or more J b ; 
 each R is independently —H or C1-C6 alkyl; and 
 each p is independently 0, 1, or 2. 
 
     
     
       2. The compound of  claim 1  wherein:
 R 1  is —H, halogen, —OR′, C1-C10 aliphatic optionally and independently substituted with one or more J a , or C3-C8 cycloaliphatic optionally and independently substituted with one or more J b . 
 
     
     
       3. The compound of  claim 1  wherein:
 R 1  is —H or —OR′. 
 
     
     
       4. The compound of  claim 1  wherein the compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 each q is independently 0 or 1; and 
 each t is independently 0, or 1-4. 
 
     
     
       5. The compound of  claim 1  wherein:
 ring B is pyridyl, pyrazinyl, pyrimidinyl, isoquinolyl, quinazolinyl, pyridopyridyl, pyridopyradazinyl, pyrrolopyridiyl, pyrazolopyridiyl, pyrolopyrimidinyl, or pyrrolopyrazinyl, wherein ring B is optionally substituted with one Y and independently further optionally and independently substituted with one or more J c . 
 
     
     
       6. The compound of  claim 1  wherein:
 ring B is pyridyl, pyrazinyl, pyrimidinyl, isoquinolyl, pyrrolopyridiyl, pyrazolopyridiyl, pyrolopyrimidinyl, or pyrrolopyrazinyl, wherein ring B is optionally substituted with one Y and independently further optionally and independently substituted with one or more J c . 
 
     
     
       7. The compound of  claim 1  wherein:
 ring B is pyridyl optionally substituted with one Y and independently further optionally and independently substituted with one or more J c . 
 
     
     
       8. The compound of  claim 1  wherein:
 ring B is pyrazinyl optionally substituted with one Y and independently further optionally and independently substituted with one or more J c . 
 
     
     
       9. The compound of  claim 1  wherein:
 ring C is selected from the group consisting of cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cyclohexenyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazalolyl, oxadiazolyl, thiazolyl, thiadiazolyl, piperidinyl, piperizinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, azepanyl, diazepanyl, triazepanyl, azocanyl, diazocanyl, triazocanyl, indolyl, indazolyl, benzimidazolyl, quinolyl, quinoxalyl, indolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxazocanyl, oxazepanyl, azabicyclopentyl, azabicyclohexyl, azabicycloheptyl, azabicyclooctyl, azabicyclononyl, azabicyclodecyl, diazabicyclohexyl, diazabicycloheptyl, azetidinyl, isoindolinyl, isoindolyl, dihydroindazolyl, dihydrobenzimidazolyl, morpholinyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyrazinyl, dihydropyrazinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydropyrazolyl, dihydroimidazolyl, octahydropyrrolopyrazyl, octahydropyrrolopyridyl, octahydropyridopyrazyl, octahydropyridopyridyl, diazabicyclooctyl, diazabicyclononyl, diazabicyclodecyl, thiazepanyl, and thiazocanyl wherein each ring is optionally substituted with one Z and independently further optionally and independently substituted with one or more J b . 
 
     
     
       10. The compound of  claim 1  wherein
 ring C is selected from the group consisting of cyclohexyl, diazabicyclooctyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazalolyl, oxadiazolyl, thiazolyl, azetidinyl, morpholinyl, azepanyl, diazabicycloheptyl, diazabicyclooctyl, indolyl, tetrahydropyridyl, dihydropyridyl, octahydropyrrolopyrazyl, octahydropyrrolopyridyl, octahydropyridopyrazyl, octahydropyridopyridyl, thiadiazolyl, piperidinyl, piperazinyl, pyrrolidinyl, diazepanyl, and oxazepanyl wherein each ring is optionally substituted with one Z and independently further optionally and independently substituted with one or more J b . 
 
     
     
       11. The compound of  claim 1  wherein
 ring C is selected from the group consisting of cyclohexyl, 3,8-diazabicyclo[3.2.1]octane, phenyl, pyridyl, piperidinyl, piperazinyl, diazepanyl, pyrrolidinyl, pyrrolyl, pyrrazolyl, azetidinyl, morpholinyl, azepanyl, 2,5 diazabicycloheptyl, diazabicyclooctyl, indolyl, tetrahydropyridyl, octahydro-1H-pyrrolo[2,3-b]pyrazyl, octahydropyrrolo[1,2-a]pyrazyl, and oxazepanyl wherein each ring is optionally substituted with one Z and independently further optionally and independently substituted with one or more J b . 
 
     
     
       12. The compound of  claim 1  wherein
 ring C is selected from the group consisting of piperidinyl, piperazinyl, diazapanyl, pyrrolidinyl, azetidinyl, and azepanyl, wherein each ring is optionally substituted with one Z and independently further optionally and independently substituted with one or more J b . 
 
     
     
       13. The compound of  claim 1  wherein ring C is represented a structural formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         q is 0 or 1; and 
         t is 0 or 1-4. 
       
     
     
       14. The compound of  claim 1  wherein ring C is represented by a structural formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         q is 0 or 1; and 
         t is 0 or 1-4. 
       
     
     
       15. The compound of  claim 1  wherein ring C is represented by a structural formula represented by: 
       
         
           
           
               
               
           
         
         q is 0 or 1; and 
         t is 0 or 1-4. 
       
     
     
       16. The compound of  claim 1  wherein ring C is represented by a structural formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         q is 0 or 1; and 
         t is 0 or 1-4. 
       
     
     
       17. The compound of  claim 1  wherein ring C is represented by a structural formula represented by: 
       
         
           
           
               
               
           
         
         q is 0 or 1; and 
         t is 0 or 1-4. 
       
     
     
       18. The compound of  claim 1  wherein ring C is represented by a structural formula represented by: 
       
         
           
           
               
               
           
         
         q is 0 or 1; and 
         t is 0 or 1-4. 
       
     
     
       19. The compound of  claim 18  wherein:
 q is 1. 
 
     
     
       20. The compound of  claim 1  wherein the compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 T is absent, —CH 2 —, —CH(J b )-, —C(J b ) 2 -, —NH— or —N(J b )-; 
 t is 0, 1, or 2; 
 n is 0 or 1; 
 w is 0 or 1; 
 J c  is CN, F, Cl, —OR, —CH 2 OR, or CF 3 ; 
 U is Z or J b    
 Z is Y2-Q2; 
 Y2 is absent or C1-6 alkyl optionally and independently substituted with one or more J d ; 
 Q2 is absent or C3-C8 cycloalkyl having 0-1 heteroatoms optionally and independently substituted with one or more J e ; wherein Y2 and Q2 are not both absent; 
 each J b  is independently F, —CN, —CF 3 , —OR, —N(R) 2 , —C(O)N(R) 2 , C1-6 alkyl optionally and independently substituted with one or more J a ; 
 each J a  is independently F, —OR, —N(R) 2 , or —C(O)N(R) 2 ; 
 each J d  is independently —OH, —CN, —C(O)N(R) 2 , —NH 2  or F; and 
 each J e  is independently C1-C6 alkyl, —OH, —CF 3 , —N(R) 2  or F. 
 
     
     
       21. The compound of  claim 20  wherein:
 T is absent, —CH(NH 2 )—, or —NH—. 
 
     
     
       22. The compound of  claim 1  wherein the compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 T is absent, —CH 2 —, —CH(J b )- , —C(J b ) 2 -, —NH— or —N(J b )-; 
 t is 0, 1, or 2; 
 w is 0 or 1; 
 J c  is OR, CH 2 OR, CN, F, Cl, or CF 3 ; 
 U is Z or J b    
 Z is Y2-Q2; 
 Y2 is absent or C1-6 alkyl optionally and independently substituted with one or more J d ; 
 Q2 is absent or C3-C8 cycloalkyl having 0-1 heteroatoms optionally and independently substituted with one or more J e ; 
 each J b  is independently F, —CN, —CF 3 , —OR, —N(R) 2 , —C(O)N(R) 2 , C1-6 alkyl optionally and independently substituted with one or more J a ; 
 each J a  is independently F, —OR, —N(R) 2 , or —C(O)N(R) 2 ; 
 each J d  is independently —OH, —CN, —C(O)N(R) 2 , —NH 2  or F; and 
 each J e  is independently C1-C6 alkyl, —OH, —CF 3 , —N(R) 2  or F. 
 
     
     
       23. The compound of  claim 22  wherein:
 T is absent, —CH(NH 2 )—, or —NH—. 
 
     
     
       24. The compound of  claim 1  wherein the compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 T is absent, —CH 2 —, —CH(J b )- , —C(J b ) 2 -, —NH— or —N(J b )-; 
 t is 0, 1, or 2; 
 w is 0 or 1; 
 J c  is —OR, —CH 2 OR, CN, F, CF 3 , CH 2 (CH 3 )OH, or 
 
       
         
           
           
               
               
           
         
         U is Z or J b    
         Z is Y2-Q2; 
         Y2 is absent or C1-6 alkyl optionally and independently substituted with one or more J d ; 
         Q2 is absent or C3-C8 cycloalkyl having 0-1 heteroatoms optionally and independently substituted with one or more J e ; 
         each J b  is independently F, —CN, —CF 3 , —OR, —N(R) 2 , —C(O)N(R) 2 , C1-6 alkyl optionally and independently substituted with one or more J a ; 
         each J a  is independently F, —OR, —N(R) 2 , or —C(O)N(R) 2 ,; 
         each J d  is independently —OH, —CN, —C(O)N(R) 2 , —NH 2  or F; and 
         each J e  is independently C1-C6 alkyl, —OH, —CF 3 , —N(R) 2  or F. 
       
     
     
       25. The compound of  claim 24  wherein:
 T is absent, —CH(NH 2 )—, or —NH—. 
 
     
     
       26. A compound represented by a structural formula selected from the group consisting of: 
       
         
           
                 
                 
               
                     
                 
                   1 
                   2 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
               
               
                
                
               
            
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       27. A composition comprising a compound or pharmaceutically acceptable salt thereof according to  claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
       28. A method of treating or preventing a protein kinase-mediated condition in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt thereof of  claim 1 . 
     
     
       29. The method of  claim 28 , wherein the protein kinase-mediated condition is a PKC mediated condition. 
     
     
       30. The method of  claim 29  wherein the PKC-mediated condition is a PKCtheta mediated condition. 
     
     
       31. The method of  claim 30 , wherein the PKCtheta mediated condition is an autoimmune disease, an inflammatory disease or a proliferative or hyperproliferative disease. 
     
     
       32. The method of  claim 31 , wherein the PKCtheta mediated condition is selected from the group consisting of asthma, psoriasis, arthritis, rheumatoid arthritis, joint inflammation, multiple sclerosis, diabetes, inflammatory bowel disease, transplant rejection, T-cell leukaemias, lymphomas, and lupus.